Over 200,000 individuals are diagnosed with lung cancer in the U.S. every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from post-menopausal women who participated in the Women's Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound impact of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.
Sitapriya Moorthi, Amy Paguirigan, Pushpa Itagi, Minjeong Ko, Mary Pettinger, Anna C. Hoge, Anwesha Nag, Neil A. Patel, Feinan Wu, Cassie Sather, Kevin M. Levine, Matthew P. Fitzgibbon, Aaron R. Thorner, Garnet L. Anderson, Gavin Ha, Alice H. Berger
The development of targeted therapies offers new hope for patients affected by incurable cancer. However, multiple challenges persist, notably in controlling tumor cell plasticity in patients with refractory and metastatic illness. Neuroblastoma (NB) is an aggressive pediatric malignancy originating from defective differentiation of neural crest–derived progenitors with oncogenic activity due to genetic and epigenetic alterations and remains a clinical challenge for high-risk patients. To identify critical genes driving NB aggressiveness, we performed combined chromatin and transcriptome analyses on matched patient-derived xenografts (PDXs), spheroids, and differentiated adherent cultures derived from metastatic MYCN nonamplified tumors. Bone marrow kinase on chromosome X (BMX) was identified among the most differentially regulated genes in PDXs and spheroids versus adherent models. BMX expression correlated with high tumor stage and poor patient survival and was crucial to the maintenance of the self-renewal and tumorigenic potential of NB spheroids. Moreover, BMX expression positively correlated with the mesenchymal NB cell phenotype, previously associated with increased chemoresistance. Finally, BMX inhibitors readily reversed this cellular state, increased the sensitivity of NB spheroids toward chemotherapy, and partially reduced tumor growth in a preclinical NB model. Altogether, our study identifies BMX as a promising innovative therapeutic target for patients with high-risk MYCN nonamplified NB.
Santhoshkumar Sundaramoorthy, Daniele Filippo Colombo, Rajendran Sanalkumar, Liliane Broye, Katia Balmas Bourloud, Gaylor Boulay, Luisa Cironi, Ivan Stamenkovic, Raffaele Renella, Fabien Kuttler, Gerardo Turcatti, Miguel N. Rivera, Annick Mühlethaler-Mottet, Anaïs Flore Bardet, Nicolò Riggi
Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.
David Lauer, Cheryl Y. Magnin, Luca R. Kolly, Huijuan Wang, Matthias Brunner, Mamta Chabria, Grazia M. Cereghetti, Hubert S. Gabryś, Stephanie Tanadini-Lang, Anne-Christine Uldry, Manfred Heller, Stijn E. Verleden, Kerstin Klein, Adela-Cristina Sarbu, Manuela Funke-Chambour, Lukas Ebner, Oliver Distler, Britta Maurer, Janine Gote-Schniering
The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir–treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.
Chao Zhou, Shun Li, Na Qiu, Ping Sun, Milton H. Hamblin, C. Edward Dixon, Jun Chen, Ke-Jie Yin
Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis have potential as anti-fibrotic agents. We identify the collagen chaperone cyclophilin B as a major cellular target of the natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Mechanistically, SfA inhibits and induces the secretion of cyclophilin B from the endoplasmic reticulum (ER) and prevents TGF-β1–activated myofibroblasts from synthesizing and secreting collagen type I in vitro, without inducing ER stress, affecting collagen type I mRNA transcription, myofibroblast migration, contractility, or TGF-β1 signaling. In vivo, SfA induced cyclophilin B secretion in preclinical models of fibrosis, thereby inhibiting collagen synthesis from fibrotic fibroblasts and mitigating the development of lung and skin fibrosis in mice. Ex vivo, SfA induces cyclophilin B secretion and inhibits collagen type I secretion from fibrotic human lung fibroblasts and samples from patients with idiopathic pulmonary fibrosis (IPF). Taken together, we provide chemical, molecular, functional, and translational evidence for demonstrating direct anti-fibrotic activities of SfA in preclinical and human ex vivo fibrotic models. Our results identify the cellular target of SfA, the collagen chaperone cyclophilin B, as a mechanistic target for the treatment of organ fibrosis.
Hope A. Flaxman, Maria-Anna Chrysovergi, Hongwei Han, Farah Kabir, Rachael T. Lister, Chia-Fu Chang, Robert Yvon, Katharine E. Black, Andreas Weigert, Rajkumar Savai, Alejandro Egea-Zorrilla, Ana Pardo-Saganta, David Lagares, Christina M. Woo
A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and DNASE1L3 deficiency, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association includes an ultra-rare pediatric population with DNASE1L3 deficiency who develop SLE, adult patients with loss of function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies to DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1–/–/Dnase1L3–/– double knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degrades genomic and mitochondrial cell free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.
Paul R. Stabach, Dominique Sims, Eduardo Gomez-Bañuelos, Sandra Zehentmeier, Kris Dammen-Brower, Andrew Bernhisel, Sophia E. Kujawski, Sam G. Lopez, Michelle Petri, Daniel W. Goldman, Ethan R. Lester, Quan Le, Tayyaba Ishaq, Hana Kim, Shivani Srivastava, Deepika Kumar, Joao P. Pereira, Kevin J. Yarema, Fotios Koumpouras, Felipe Andrade, Demetrios T. Braddock
Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here we show that ferroptosis negative regulation (FNR) signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/4EBP1 signaling promoted SLC7A11 protein synthesis, leading to ferroptosis inhibition in MEK inhibitor resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR-4EBP1 activity to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
Jiaxin Yin, Jianfeng Chen, Jing Han Hong, Yulin Huang, Rong Xiao, Shini Liu, Peng Deng, Yichen Sun, Kelila Xin Ye Chai, Xian Zeng, Jason Yongsheng Chan, Peiyong Guan, Yali Wang, Peili Wang, Chongjie Tong, Qiang Yu, Xiaojun Xia, Choon Kiat Ong, Bin Tean Teh, Ying Xiong, Jing Tan
This study lays the groundwork for future lentivirus-mediated gene therapy in patients with Diamond Blackfan anemia (DBA) caused by mutations in ribosomal protein S19 (RPS19), showing evidence of a new safe and effective therapy. The data show that, unlike patients with Fanconi anemia (FA), the hematopoietic stem cell (HSC) reservoir of patients with DBA was not significantly reduced, suggesting that collection of these cells should not constitute a remarkable restriction for DBA gene therapy. Subsequently, 2 clinically applicable lentiviral vectors were developed. In the former lentiviral vector, PGK.CoRPS19 LV, a codon-optimized version of RPS19 was driven by the phosphoglycerate kinase promoter (PGK) already used in different gene therapy trials, including FA gene therapy. In the latter one, EF1α.CoRPS19 LV, RPS19 expression was driven by the elongation factor alpha short promoter, EF1α(s). Preclinical experiments showed that transduction of DBA patient CD34+ cells with the PGK.CoRPS19 LV restored erythroid differentiation, and demonstrated the long-term repopulating properties of corrected DBA CD34+ cells, providing evidence of improved erythroid maturation. Concomitantly, long-term restoration of ribosomal biogenesis was verified using a potentially novel method applicable to patients’ blood cells, based on ribosomal RNA methylation analyses. Finally, in vivo safety studies and proviral insertion site analyses showed that lentivirus-mediated gene therapy was nontoxic.
Yari Giménez, Manuel Palacios, Rebeca Sánchez-Domínguez, Christiane Zorbas, Jorge Peral, Alexander Puzik, Laura Ugalde, Omaira Alberquilla, Mariela Villanueva, Paula Río, Eva Gálvez, Lydie Da Costa, Marion Strullu, Albert Catala, Anna Ruiz-Llobet, Jose Carlos Segovia, Julián Sevilla, Brigitte Strahm, Charlotte M. Niemeyer, Cristina Beléndez, Thierry Leblanc, Denis L.J. Lafontaine, Juan Bueren, Susana Navarro
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that two distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice liver, dual AAV gene therapy combined with rapamycin reduced the impact of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and support clinical translation.
Louisa Jauze, Mallaury Vie, Quentin Miagoux, Lucille Rossiaud, Patrice Vidal, Valle Montalvo-Romeral, Hanadi Saliba, Margot Jarrige, Helene Polveche, Justine Nozi, Pierre-Romain Le Brun, Luca Bocchialini, Amandine Francois, Jeremie Cosette, Jérémy Rouillon, Fanny Collaud, Fanny Bordier, Emilie Bertil-Froidevaux, Christophe Georger, Laetitia Van Wittenberghe, Adeline Miranda, Nathalie Daniele, David Gross, Lucile Hoch, Xavier Nissan, Giuseppe Ronzitti
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration — a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.
Deepak Sharma, Darbaz Adnan, Mostafa K. Abdel-Reheem, Ron C. Anafi, Daniel D. Leary, Faraz Bishehsari
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